The present invention relates generally to the field of organic synthesis and stereochemical assignments of compounds exhibiting efficacy against neoplastic diseases.
Natural products that elicit a specific and unique biological response in mammalian cells represent valuable tools for new pharmaceuticals for the treatment for various disease states. In this context the recent isolation of irciniastatin and psymberin from the marine sponges Ircinia ramose and Psammocinia sp respectively is noteworthy. Both irciniastatins and psymberin have potent inhibitory activity in human tumor cell assays. They also have partial structural resemblance to the pederin family of natural products and therefore could share the latter's well-documented pharmacological role as potent eukaryotic protein synthesis inhibitors. The total synthesis of these natural products, analogs thereof, and probe-reagents for mode-of-action studies should provide a solid foundation for lead identification and preclinical studies in the area of human cancer.
In 2004, two research groups led by Pettit and Crews independently disclosed the isolation of structurally novel, constitutionally identical cytotoxins. Both irciniastatin and psymberin (shown below) were isolated based on their potent inhibitory activity in human tumor cell assays. Irciniastatin A was isolated from the Indo-Pacific marine sponge Ircinia ramose (Pettit, G. R. et al. J. Med. Chem. 2004, 47, 1149), whereas psymberin was obtained from a marine sponge Psammocinia sp. collected from the waters of Papua New Guinea (Cichewicz, R. H. et al. Org. Lett. 2004, 6, 1951). See also WO 2005/054809.

High field multidimensional NMR studies and chiroptical data (Circular Dichroism; Cotton effect at n→Π* transition of dihydroisocoumarin) substantiated the proposed relative and absolute configuration for psymberin, except for the undefined configuration at C4 (Cichewicz, R. H. et al., supra). The relative stereochemistry of irciniastatin A was only resolved for the C8-C13 aminal fragment (Pettit, G. R. et al., supra). Notably, the C8-aminal configuration in irciniastatin A (based on nOe-data) was opposite to the corresponding center assigned for psymberin. No copies of actual NMR spectra were included in the irciniastatin publication (Pettit, G. R. et al., supra) and, combined with the fact that spectra for irciniastatin and psymberin were acquired in different NMR solvents, no conclusion could be drawn whether these two constitutionally ident ical metabolites bear an identical or diastereomeric correspondence. Therefore, a need exists to define the stereochemistry of these purified active cytotoxins, together with synthetic routes to make them.